Every year, 16,000 cases of lupus are reported in the United States — 9 out of 10 of them in women. Scientists have long believed sex differences help explain women’s predisposition for the autoimmune disease. But researchers said last week that they may now have one explanation for why exactly the presence of two X chromosomes increases the chances that a person will develop lupus.
Dozens of genes have been associated with lupus, but in a new study, researchers focused on the overexpression of the gene Tlr7, which sits on the X chromosome.
In women’s cells, genes on one of the X chromosomes become inactivated as a way of controlling gene expression. In the study, published Friday in the journal Science Immunology, a team of French scientists found that Tlr7 can evade attempts to limit its expression.
“This was a hypothesis that you found in many reviews, but it had never been demonstrated,” said Jean-Charles Guéry, a study author and scientist at Inserm, France’s equivalent of the National Institutes of Health.
Patients with lupus suffer from pain, fever, and rashes in different parts of their bodies, with the symptoms coming and going as the disease flares. There is no cure, but it is managed with medications that target inflammation and tamp down immune system activity.
For their study, researchers studied the immune cells of healthy women, measuring the expression of Tlr7. They found that in some cells, both copies of the gene were making the protein TLR7. They found the same pattern of dual expression when studying cells of men who have an extra X chromosome, what is called Klinefelter syndrome. (Men with Klinefelter syndrome develop lupus at much higher rates than other men.)
That indicated that Tlr7 was able to avoid X chromosome inactivation.
The researchers also discovered that the overexpression of Tlr7 — what is called biallelism, because both alleles are being expressed — led to changes in the cells and the proteins they produce that could induce autoimmune issues. The protein TLR7 normally plays a role in helping the immune system identify viral infections, but in past animal studies, researchers have found that when immune cells produce excess TLR7, the animals can develop their version of lupus.
Dr. Hal Scofield, an autoimmune disease expert at the Oklahoma Medical Research Foundation who was not involved in the new study, said it bolstered the belief that having more TLR7 increases the chances of developing lupus. But he noted that there are dozens of genes associated with lupus, and that even people genetically predisposed to the disease might not develop it.
Still, Scofield said, the study pointed to the importance of X chromosome inactivation, which has often been underestimated. He said that if both copies of Tlr7 are expressed, then maybe other, related genes also associated with lupus get overexpressed.
“Given all the genes that escape X inactivation, there might be others,” he said. “You might find others that interact with TLR7. You might find a whole cascade.”
Guéry said he and his team next plan to compare TLR7 levels in healthy women with those in lupus patients. He wondered, for example, if higher levels of the protein might be correlated to the severity of the disease or the onset of flares of symptoms.
Guéry said his research did not show how or why exactly Tlr7 avoids X chromosome inactivation, but that it suggested limiting TLR7 levels might offer a new therapeutic avenue to treating lupus — a step that would be easier than trying to inactivate the second copy of the Tlr7 gene.
“It’s true that if we can reestablish inactivation of the X chromosome, that might be good for patients,” he said. “But what might be better is to target TLR7 directly.”